With great interest, we read the paper written by Brem and Karran concerning the unravelling of a novel pathway of toxicity during 6-thioguanine (6-TG) administration. The thiopurine 6-TG itself acts as a source of reactive oxygen species (ROS), which in combination with incorporated 6-TG nucleotides in DNA leads to cell killing (1). Interestingly, the coadministration of allopurinol protects cells from cytotoxicity by avoiding a decrease in the protective glutathione concentrations through scavenging of ROS. Whether this implicates that the concomitant use of allopurinol restrains 6-TG effectiveness in vivo is unclear.
The conventional thiopurines, azathioprine and 6-mercaptopurine, are frequently used for the treatment of malignancies and immune-mediated inflammatory diseases. Their administration on the short term is often limited by the development of intractable adverse events and ineffectiveness, which in part is related to a deviant drug metabolism characterized by elevated concentrations of methylated thiopurine metabolites [6-methylmercaptopurine (6-MMP)]. Whether these adverse events reflect an increment in the oxidative stress remains speculative. Over the past years, the combination of allopurinol with low-dose azathioprine or 6-mercaptopurine has successfully been used to bypass these 6-MMP–associated adverse events and to increase therapeutic efficacy (2). More specifically, upon combination therapy, 6-MMP concentrations decrease drastically, whereas concentrations of the pharmacologically active 6-TG nucleotides increase. Because the mechanism of this interaction remains largely elusive, it is of particular interest whether (a reduction of) oxidative stress may be involved. The long-term administration of thiopurines is hampered by the risk and fear of developing (secondary) cancer, like skin cancer, leukemia, and lymphoma (3, 4). The ROS-mediated cytotoxicity of 6-TG, as shown by Brem and Karran, may contribute to this carcinogenesis. This may also hold true for the more frequently used azathioprine and 6-mercaptopurine. In their experiments, allopurinol showed antioxidant properties and protected against DNA damage. The avoidance of DNA damage by precluding depletion of glutathione owing to allopurinol coadministration may well lead to a lowered risk of developing thiopurine therapy–induced cancer.
In conclusion, allopurinol not only possesses thiopurine metabolism modulating properties but also ROS scavenging and subsequently DNA damage preventing properties. Prospective and controlled studies are warranted to further explore the potential beneficial role of adding allopurinol as a routine alongside thiopurines.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
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